This invention relates generally to novel bicyclic hydroxamates as inhibitors of matrix metalloproteinases (MMP), TNF-xcex1 converting enzyme (TACE), aggrecanase or a combination thereof, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 1970, 52A, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 1978, 21, 761-766, Woessner et al. Arthritis Rheum. 1983, 26, 63-68 and Woessner et al. Arthritis Rheum. 1984, 27, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 1993, 36, 1214-22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 1990, 25, 175-184, AP, San Diego).
Tumor necrosis factor-xcex1 (TNF-xcex1) is a cell-associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF-xcex1 has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-xcex1 has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-xcex1 with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander, L. S. et al. Arthritis Rheum. 1993, 36, 1214-22) and Crohn""s disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNF-a converting enzyme (TACE), the enzyme responsible for TNF-xcex1 release from cells, were purified and sequenced (Black et al Nature 1997, 385, 729; {dot over (M)}oss et al Nature 1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF-xcex1 production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-xcex1 production may also have a particular advantage in diseases where both mechanisms are involved.
Prostaglandins (PG) play a major role in the inflammation process and the inhibition of PG production has been a common target of anti-inflammatory drug discovery. Many NSAIDS have been found to prevent the production of PG by inhibiting the enzyme cyclooxygenase (COX). Among the two isoforms of COXs, COX-1 is constitutively expressed. COX-2 is an inducible isozyme associated with inflammation. Selective COX-2 inhibitor was believed to maintain the efficacy of traditional NSAIDs, which inhibit both isozymes, and produce fewer and less drastic side effects. As a result, development of selective COX-2 inhibitors has attracted major interest in the pharmaceutical industry. Because of the significant roles of PGs and TNF-xcex1 in inflammation, combined use of COX-2 and TACE inhibitors may have superior efficacy to either therapy alone in some inflammatory diseases.
U.S. Pat. Nos. 5,506,242, 5,552,419, and 5,672,615 disclose matrix metalloproteases inhibitors of the formula: 
wherein Ar is carbocyclic or heterocyclic aryl; R and R1 together with the chain to which they are attached form a 1,2,3,4-tetrahydroisoquinoline; R2 can be hydrogen. The compounds of U.S. Pat. Nos. 5,506,242, 5,552,419, and 5,672,615 are not considered to be part of the presently claimed invention.
WO97/18194 (U.S. Pat. No. 6,207,672) depicts matrix metalloproteases inhibitors of the formula: 
wherein A can be HOxe2x80x94NHxe2x80x94C(O)xe2x80x94; R1 can be R2xe2x80x94Xxe2x80x94Phxe2x80x94Bxe2x80x94; X is a bond or a single chain atom spacer; R2 is unsubstituted or substituted phenyl; and, Q forms a ring as defined in WO97/18194. These compounds are not considered to be part of the present invention.
WO98/08850 illustrates matrix metalloproteases inhibitors of the formula: 
wherein R1 is hydrogen; R2 can be hydrogen; W can be arylene or heteroarylene bridge between two adjacent carbons forming a fused ring. These compounds are not considered to be part of the present invention.
DE 19542189 presents matrix metalloproteases inhibitors of the formula: 
wherein R1 can be R5xe2x80x94Xxe2x80x94Phxe2x80x94Axe2x80x94; A is C1-4 alkylene or xe2x80x94CHxe2x95x90CHxe2x80x94; X is a bond or a single chain atom spacer. These compounds are not considered to be part of the present invention.
U.S. Pat. No. 5,866,587 describes matrix metalloproteases inhibitors of the formula: 
wherein m and n are identical or different, represent 0, 1, 2; A represents an aryl ring or heterocycle; X represents xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94SO2NHxe2x80x94; and R5 represents optionally substituted alkyl, (C3-7)cycloalkyl, aryl or heterocyclic. These compounds are not considered to be part of the present invention.
U.S. Pat. No. 5,962,471 describes matrix metalloproteases inhibitors of the formula: 
wherein R1 is unsubstituted or substituted phenyl or hetereocycle; A is a bond, O, xe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94; B is C1-3 alkylene, xe2x80x94Oxe2x80x94C1-5 alkylene- or xe2x80x94CHxe2x95x90CHxe2x80x94; X is xe2x80x94CHxe2x95x90CHxe2x80x94, oxygen or sulfur; and R2 can be HO(H)Nxe2x80x94. These compounds are not considered to be part of the present invention.
U.S. Pat. No. 6,225,311 discloses hydroxamic acid derivatives of the formula: 
wherein X can be SO2; Y is aryl or heteroaryl; Z can be O, NH, CH2 or S; R2 can be hydrogen; R4 and R5 can be hydrogen; and R1 and R3 together with the atoms to which they are attached can form a divalent moiety of the formula: 
wherein A is aryl or heteroaryl. These compounds are defined as being useful as TACE and MMP inhibitors. These compounds are not considered to be part of the present invention.
WO00/23443 illustrates TNF-xcex1 production inhibitors of the formula: 
wherein R1 is an optionally substituted C1-6 alkyl, phenyl, or heteroaryl. These compounds are not considered to be part of the present invention.
WO00/44730 depicts hydroxamic acid derivatives of the formula: 
These compounds are defined as being useful as TACE and MMP inhibitors. These compounds are not considered to be part of the present invention.
EP 1065209 describes matrix metalloproteases inhibitors of the formula: 
wherein R2 can be xe2x80x94NHOH; and Ar1 can be phenyl. These compounds are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular TACE, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TACE, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
Accordingly, the present invention provides novel bicyclic hydroxamates useful as MMP and/or TACE inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method of treating a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
The present invention provides a method for treating inflammatory disorders, comprising: administering, to a host in need of such treatment, a therapeutically effective amount of one of the compounds of the present invention, in combination with one or more additional anti-inflammatory agents selected from selective COX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAP kinase inhibitors, TNF-xcex1 inhibitors, TNF-xcex1 sequestration agents, and methotrexate.
The present invention provides novel compounds of the present invention for use in therapy.
The present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, B1, B2, R1, and C are defined below, are effective MMP and/or TACE inhibitors.